AB0140 ROLE OF ENDOGLIN IN THE PATHOGENESIS OF SYSTEMIC SCLEROSIS: A PRISMA-DRIVEN SYSTEMATIC REVIEW
Authors: S. Grignaschi, B. L. Palermo, G. Spinozzi, A. Sbalchiero, C. Cantarini, C. Nardiello, C. Olivieri, L. Cavagna
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic sclerosis (SSc) is a rare autoimmune disease characterized from peculiar vascular alteration and fibrosis of the skin and internal tissues. SSc pathogenetic mechanisms are still partially unclear but an involvement of the TGFβ pathway, known for being responsible of both angiogenesis and fibrosis, has been proven. Endoglin (ENG) is a TGFβ receptor type III involved in signal regulation, and mutations in ENG gene cause Hereditary Hemorrhagic Telangiectasia type I, a rare disease that shares with SSc the presence of mucocutaneous telangiectasias and disturbed angiogenesis. Objectives The aim of this systematic review is to highlight the role of ENG in the pathogenesis of SSc focusing on a subset of clinical manifestations. Methods We performed a systematic review following the PRISMA guidelines, searching the MEDLINE (PubMed), Web of Science and EMBASE databases using as keywords: “Endoglin”, “sENG”, “CD105”, “Systemic sclerosis”, “SSc”, “Scleroderma”, “CREST”. The last search was made on November 2 nd 2021. This review includes both conference abstracts (without subsequent publication) and articles that evaluated the relationships between SSc and ENG; we excluded the papers that used CD105 only as a cell marker. We then consulted the references from the papers found in order to search possible articles that escaped our first search. Results Of the 656 records identified from the database research, 42 were included in our systematic review (16 abstracts and 26 original papers) (Figure). The majority of these studies (25) measured serum ENG (sENG) looking for correlations with cutaneous, pulmonary and cardiac disease in patients with SSc. Figure. PRISMA flow diagram. High levels of sENG demonstrated an independent association with telangiectasia in 2 studies, with the presence of digital ulcers (DU) in 6 studies but was not related to the occurrence of new DU (2 studies) and it was related to scleroderma pattern late in 2 studies. Between limited and diffuse cutaneous SSc, sENG showed no differences in one study and significantly higher values in lcSSc in another, this latter study also found sENG to be higher in lcSSC compared to systemic lupus erythematous and healthy controls (HC). sENG, moreover, demonstrated a positive correlation with anti-centromere antibodies (two studies). Regarding pulmonary involvement, no correlation between sENG and mean pulmonary arterial pressure was recorded, and two studies found sENG elevated in patients with pulmonary arterial hypertension while no correlation was found from two other papers. High sENG concentrations demonstrated a positive correlation with subclinical atherosclerosis and with high sensitivity troponin, but its concentration did not relate to right heart dysfunction (1 study each). Two different groups evaluated sENG concentration in Localized Scleroderma and found no differences with other connective tissue diseases. One study searched for genetic alterations in the expression of ENG gene and found no difference between SSc patients and HC. Four studies evaluated Eng expression on fibroblast surface: SSc fibroblasts from both systemic circulation and lung showed higher production of Eng than HC. Tissue Eng, moreover, is up regulated in SSc patients where it acts as a regulator of TGFβ signaling and of extracellular matrix production. Conclusion As suggested by the role of Endoglin in the TGFβ pathway, several authors demonstrated an altered expression of Endoglin in SSc patients. A particular focus of interest is the role of ENG in PAH and DU that occur in SSc. A direct involvement of ENG in PAH is known as mutation in this gene are one of the genetic causes of PAH. However, particularly in pulmonary vascular disease, there are still controversial and insufficient data to draw definitive conclusions. As PAH is a leading cause of mortality in SSc patients this is an area of clinical interest and the study of the TGFβ pathway could lead to useful clinical findings. Disclosure of Interests None declared